2009.01.30 – Treatment of Hematological Malignancies

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The American Society of Clinical Oncology 2008: Highlights of Treatment of Hematological Malignancies
CancerConsultants.com – News 1/30/2009
The 2008 annual meeting of the American Society of Clinical Oncology (ASCO), held in Chicago, Illinois, again revealed advances in the treatment of hematologic malignancies. Patients with chronic or acute leukemias, myelodysplastic syndromes, and myeloproliferative disorders continue to be presented with novel, effective options for the treatment of their diseases.
In addition, treatment targeted against specific disease characteristics continues to progress at a rapid pace. Alongside this progress comes a better understanding of the role of standard therapies for patients with these diseases.
Treatment of Chronic Myelogenous Leukemia
Imatinib mesylate is the standard initial treatment of newly diagnosed chronic myelogenous leukemia (CML). Imatinib produces high rates of complete cytogenetic responses (70-85%) and of major molecular responses (20-40%) and has improved progression-free and overall survival.1 2 However, imatinib does not eradicate the BCR-ABL clones in most patients as detected by polymerase chain reaction (PCR) monitoring. Furthermore, a small but significant fraction of patients will develop imatinib resistance or are intolerant to the drug. Patients who fail or are intolerant to imatinib now have treatment alternatives other than allogeneic stem cell transplantation.
Dasatinib and nilotinib are two new agents that have been developed for the treatment of patients with BCR-ABL-positive CML and acute lymphoblastic leukemia (ALL) that appear to have great promise for the treatment of patients who fail imatinib. Dasatinib and nilotinib are both approved by the U.S. Food and Drug Administration for treatment of patients who fail or are intolerant to imatinib. Other tyrosine kinase inhibitors are under development and being tested in the clinic. At ASCO 2008, updated data were presented on both these agents.
Dasatinib for Patients Who Fail or Are Intolerant to Imatinib
Researchers affiliated with the START-C (CA180-013) international multi-center study reported updated outcomes of 387 patients with chronic-phase CML and resistance or intolerance to imatinib who where treated with dasatinib.3 Median time from diagnosis to treatment with dasatinib was 61 months; 65% had also received interferon, 10% had received a stem cell transplant, and 55% had received 600 mg/day or more of imatinib. The minimal follow-up time for this group of patients is now 24 months. The major findings were:
• Complete hematologic remission in 91%
• Major cytogenetic response in 62%
• Complete cytogenetic response rin 53%
• Major molecular response in 47%
• Major cytogenetic response in 55% of imatinib-resistant patients
• Major cytogenetic responses in 63% of patients with BCR-ABL mutations
• Complete cytogenetic response rate of 78% for imatinib-intolerant patients
• Major molecular response rate of 78% for imatinib-tolerant patients
• Major cytogenetic response maintained for at least 24 months in 88%
• Two-year progression-free survival of 80%
• Two-year overall survival of 94% (100% for imatinib-intolerant patients)
Dose interruptions were required for the majority of patients. There were few new toxicities occurring between 12 and 24 months of treatment. The authors conclude that dasatinib was well tolerated and that cytogenetic responses were durable.
Researchers affiliated with the START-R (CA180-017) international multi-center study reported that dasatinib is more effective than imatinib 800 mg/day for patients with CML in chronic phase who are resistant to imatinib 400-600 mg/day.4 One-hundred-fifty patients with CML who were resistant to standard doses of imatinib but still in chronic phase were randomly allocated on a 2:1 basis to receive dasatinib 700 or 800 mg/day of imatinib. The minimum follow-up for this study is now 24 months. The following table summarizes the main findings of this trial:
Table 1: Dasatinib Versus Imatinib in CML

Dasatinib
High-Dose Imatinib
Number of Patients
101
49
Major Cytogenetic Response
53%
33%
Complete Cytogenetic Response (MCyR)
44%
18%
Major Molecular Response
29%
12%
MCyR at 18 months
90%
74%
2-year Progression-Free Survival
86%
65%
2-year Failure Rate
41%
82%
Therapy Discontinued for Toxicity
22%
20%
The authors concluded that dasatinib continues to show superiority over high-dose imatinib for treatment of patients resistant to imatinib.
Dasatinib for Treatment of Newly Diagnosed CML
Researchers from the M.D. Anderson Cancer Center have reported that dasatinib produced rapid and complete cytogenetic responses in a high percentage of 40 newly diagnosed patients with CML.5 Patients were randomized to be treated at a dose of 100mg/day given as a single dose or 50 mg given BID. This trial compared the rate of complete cytogenetic responses in patients receiving dasatinib or imatinib at a dose 400 or 800 mg/day. The following table summarizes the main findings to date.
Table 2: Complete Cytogenetic Responses Produced by Dasatinib in CML

% Complete Cytogenetic Response

Duration of Therapy(months)
Imatinib 400 mg/D
Imatinib 800 mg/D
Dasatinib
3
37
62
72
6
54
82
94
12
65
86
100
The authors reported that at 12 months the major molecular response rate was 32%. Dasatinib was well-tolerated. Approximately half the patients receiving dasatinib required transient interruption of treatment. The authors suggested that dasatinib produced more rapid and possibly more complete cytogenetic responses than 400 mg/day of imatinib. Dasatinib may or may not be superior to 800 mg/day of imatinib.
Nilotinib for Patients Who Fail or Are Intolerant to Imatinib
Data on 321 patients with CML in chronic phase who had resistance or intolerance to imatinib and were treated with nilotinib were presented at ASCO 2008.6 Nilotinib was administered at 400 gm BID. Seventy-one percent of patients in this study were resistant to imatinib, and 72% had receive imatinib doses >600 mg per day. The main findings were:
• The complete hematological remission rate was 91% for the 206 patients not in remission at the start of therapy.
• A major cytogenetic response was observed in 57% of patients: 55% of resistant-patients and 63% of intolerant-patients.
• 41% had a complete cytogenetic response.
• Of them, 84% maintained at least a major cytogenetic response for 18 months
• These data confirm that nilotinib is an effective treatment for patients in chronic phase who are resistant to or intolerant of imatinib.
• At 18 months the overall survival was 91%.
• More than half of all patients in the study are still receiving nilotinib.
• The most frequent toxicities were hematologic.
These follow-up data confirm the effectiveness of nilotinib for the treatment of patients with CML who have imatinib resistance or intolerance and are still in CP.
In another study 136 patients with CML in blastic phase who were resistant or intolerant to imatinib were treated with nilotinib.7 A hematological response was observed in 21% and a complete hematological response in 11%. Major cytogenetic response was observed in 40% and 29% had complete cytogenetic response. Overall survival at 12 months was 42%. Ten percent of patients in this study are still receiving nilotinib.
Treatment of CML with Bosutinib (SKI-606)
Bosutinib, a 7-alkoxy-4-[(2,4-dichloro-5-methoxyphenyl)amino-3-quinolinecarbonitrile, is a potent inhibitor of both Bcr-Abl and Src kinase activity. Researchers from Europe and the United States presented data at ASH 2007 on bosutinib treatment of patients with CML in accelerated (AP) and blast phase (BP).8 In patients with AP and no prior exposure to tyrosine kinase inhibitors, a major cytogenetic response was achieved in 3/6 patients in AP and 2/5 in BP. Four of 21 patients with prior exposure to tyrosine kinase inhibitors had a major cytogenetic response, which was complete in three. Responses occurred across and wide variety of mutations, and the toxicity profile was favorable. Side effects included diarrhea, nausea, vomiting, and abdominal pain. Grade 3 and 4 toxicities (rash, thrombocytopenia) occurred in 5% of patients.
AT ASCO 2008 researchers involved in an international study reported data on 152 patients with CML in CP who were treated with bosutinib.9 All patients in this study had resistance or intolerance to imatinib, and some had failed interferon, dasatinib, nilotinib, or an allogeneic stem cell transplant.
• The complete hematological response rate was 89% (n=39).
• The major cytogenetic response rate was 41% (n=56).
• The complete cytogenetic response rate was 30% (n=56).
• The major molecular response rate was 33% (n=58).
• The complete molecular response rate was 19% (n=58).
• 77% of patients failing dasatinib or nilotinib had a complete hematologic remission, 20% had a major cytogenetic response and 16% had a major molecular response.
• Responses were seen in patients with a variety of mutations.
• The authors describe a favorable toxicity profile with minimal hematologic toxicity.
Treatment of Chronic Lymphocytic Leukemia
Genasense® (oblimersen, Bcl-2 antisense): Researchers involved in a multicenter trial have reported that the addition of Genasense to Fludara® (fludarabine) and Cytoxan® (cyclophosphamide) improves the survival of patients with relapsed or refractory chronic lymphocytic leukemia (CLL) who achieve a complete remission (CR) or near complete remission (nCR).10
Genasense is a Bcl-2 antisense oligodeoxynucleotide that is being evaluated for the treatment of multiple myeloma, acute myeloid leukemia (AML), CLL, melanoma, and acute lymphoid leukemia (ALL). Bcl-2 is a potent inhibitor of apoptosis. Over-expression of this protein in patients with a variety of malignancies is associated with resistance to chemotherapy. Genasense down-regulates Bcl-2 and has been investigated in several hematologic malignancies where Bcl-2 has been implicated in disease resistance. In vitro studies suggest that Genasense can down-regulate Bcl-2 activity and inhibit cell viability.
Researchers from several institutions have previously reported the outcomes of 241 patients with advanced CLL treated with Fludara and Cytoxan with or without Genasense.11 The addition of Genasense increased the proportion of patients who achieve CR/nCR from 7% in the Fludara/Cytoxan only arm to 17% in the Genasense arm. Overall response rates were not different between the two groups. Maximum benefit was observed in Fludara-sensitive patients, who had a fourfold increase in the CR/nCR rate. Responses were more durable in the patients receiving Genasense. The estimated median survival in the Genasense group was 33.8 months compared with 32.9 months in the chemotherapy-only group. The estimated three-year survival rate was 46% for the Genasense group and 37.5% for the chemotherapy only group.
In the ASCO 2008 presentation, researchers reported a median duration of CR of 22 months in patients receiving Fludara and Cytoxan; the median has not been reached for patients receiving Genasense. The median survival time for patients in CR has not been reached in the Genasense group, but was reached at 46 months in the non-Genasense group. The researchers reported that 12 of the 20 patients achieving a CR were alive in the Genasense group versus three of eight patients receiving Fludara and Cyoxan without Genasense. Complete response was continuing in five of 12 in the Genasense group versus zero of three in the Fludara and Cytoxan group. It was concluded that the addition of Genasense to Fludara and Cytoxan increased the CR rate, CR duration, and survival of patients achieving CR. The authors also suggest that CR is a valuable endpoint in evaluating therapies for CLL.
Flavopiridol
Flavopiridol is a cyclin-dependent kinase inhibitor that is being evaluated as a single agent and in combination with other agents for the treatment of CLL. In one report published in 2005, flavopiridol was found to have “modest schedule-dependent clinical activity in relapsed CLL.”12 However, another study involving some of the same investigators concluded that flavopiridol had no activity in CLL.13 Studies presented at ASCO 2006 suggested that pharmacokinetic modeling was necessary for optimal effects of flavopiridol in CLL.14 15 These studies led to a regimen that consisted of a 30-minute loading dose followed by a four-hour infusion administered weekly for four to six weeks.16 The dose limiting toxicity of this regimen was hyperacute tumor lysis syndrome requiring aggressive prophylaxis and exclusion of patient with WBC counts >200 x 109/L. Forty-five percent of 42 refractory patients in this study achieved a partial response. The authors found significant activity of flavopiridol in patients with 17p13.1 cytogenetic abnormalities. They suggest that this agent is one of the most active agents in clinical trials for CLL.
At ASCO 2006 researchers presented data on the addition of flavopiridol to Fludara® (fludarabine)and Rituxan for the treatment of CLL and mantle cell lymphoma.17 In this clinical study flavopiridol was given by one hour bolus infusion in addition to Fludara and Rituxan® (rituximab). The researchers reported significant clinical activity but significant toxicity. They are modifying the flavopiridol schedule and adding Neupogen® (filgrastim) to the regimen.
At ASCO 2008 researchers treated 62 patients with relapsed CLL with flavopiridol.18 Patients in this study were pretreated with dexamethasone to block the effects of IL-6 release during therapy. All were treated with a 30-minute bolus infusion followed by a four-hour infusion. Six and a half percent had a complete response, and 42% a partial response. Responses were observed in nine of 18 patients with adverse cytogenetics. The authors concluded that flavopiridol had “pronounced” activity in patients with relapsed CLL, including patients with bulky adenopathy and poor-risk cytogenetics.
Alemtuzumab
Alemtuzumab (Campath) is very effective for the treatment of patients with CLL who have failed both alkylating agents and Fludara. Campath is a fully human monoclonal antibody that selectively targets the CD52 antigen, which is expressed more prominently on malignant lymphocytes than other cells. The binding of Campath stimulates cellular lysis of the malignant lymphocytes and reduction or elimination of cancerous cells throughout the bone marrow, blood and lymph system. In October of 2007 the US Food and Drug Administration (FDA) approved Campath for initial treatment for patients with CLL. Side effects of Campath include an increased rate of infectious complications.
At ASCO researchers from Italy reported on a regimen of subcutaneously administered low-dose Campath® (alemtuzumab) to determine if this decreased side effects.19 All patients in this study had 17p deletion and were unlikely to respond to alkylating agents. The median age for patients in this study was 74 years. The complete response rate was 7%, and the partial response rate was 33%. The median progression-free survival was 12 months for responding patients, and the median overall survival was 30 months. This regimen appeared to be well-tolerated with no infectious deaths.
Treatment of Acute Lymphoblastic Leukemia
Sprycel® (dasatinib) in patients with Philadelphia (Ph) Positive ALL (ALL): A Previous study in children suggested that the addition of Gleevec® (imatinib mesylate) to high-dose chemotherapy improves event-free survival in children with Ph+ ALL.20 Other studies have also suggested that Gleevec is an integral component of treatment for Ph+ ALL.
At ASCO 2008 researchers from M. D. Anderson Cancer Center reported outcome of 54 patients with de novo or minimally treated Ph+ ALL who were treated with hyperCVAD and Gleevec.21 All patients received Gleevec for the first 14 days of induction and continuously through courses 2-8 with indefinite maintenance. The complete response rate was 93% for the 45 patients who were not in remission at the time of study entry. The molecular CR rate was 52%. 16 patients underwent allogeneic stem cell transplantation. Overall survival rates were 70% for transplant recipients and 54% for non-transplant recipients. The authors compared the results of hyper CVAD with and without Gleevec and concluded that Gleevec improved disease-free survival from 14% to 62% and overall survival from 15% to 55%.
The incorporation of the more active tyrosine kinase inhibitors, Tasigna® (nilotinib) or Sprycel® (dasatinib) may further improve the results achieved with Gleevec. At ASCO 2008 researchers from M.D. Anderson Cancer Center reported the outcomes of 20 patients with Ph+ ALL treated with hyper CVAD and Sprycel.22 In this study patients with Ph+ ALL were treated with 14 days of Sprycel with each cycle of hyperCVAD followed by indefinite maintenance with Sprycel. Two patients died early of treatment-related complications. Seventeen patients achieved a complete remission. Fourteen of 17 evaluable patients achieved a complete cyotogenetic response. Five of 17 patients achieved a complete molecular remission. Sixteen patients are alive, and 13 are in continuous remission. Two patients died during induction therapy, one died of an unrelated cause, and one died of infection. The combination of Hyper CVAD and dasatinib appeared to be very active in patients with Ph+ ALL.
Myelodysplastic Syndromes (MDS)
The myelodysplastic syndromes (MDS) are a collection of clonally-derived hematopoietic disorders typified by peripheral blood cytopenias, transfusion-dependence, and in a subset of patients, increased likelihood of transformation to acute myeloid leukemia (AML).23 The use of the International Prognostic Scoring System (IPSS) for newly diagnosed patients has allowed objective evaluation of various new treatments for patients with MDS.24
This past decade has brought increased attention to MDS with the approval by the U.S. Food and Drug Administration of Vidaza® (azacitidine), Dacogen® (decitabine), and Revlimid® (lenalidomide), and a more complete understanding of these diseases on a molecular level.
Dacogen: Researchers from M.D. Anderson Cancer Center have previously reported that a five-day short intravenous (IV) schedule of Dacogen was optimal for the treatment of patients with MDS and chronic myelomonocytic leukemia (CMML).25 Dacogen has also been shown to improve response rates and prolong time to AML transformation and death.26 These data were confirmed in a follow-up study in patients with higher risk MDS.27
At ASCO 2008 a five-day Dacogen regimen was evaluated in the following risk IPSS groups:
• 50% of 52 patients in the Intermediate-1 risk group had improvement.
• 61% of 23 patients in the Intermediate-2 risk group had improvement.
• 43% of 23 patients in the High risk group had improvement.
• 51% of patients with de novo MDS had improvement.
• 45% of patients with secondary MDS had improvement.
• 45% of patients who had received prior therapy had improvement.
The authors concluded that the five-day short IV regimen was as effective as a three-day dosing regimen.
Myeloproliferative Syndromes
Myeloproliferative disorders currently include polycythemia vera, essential thrombocytosis, and idiopathic myelofibrosis. The cause or causes of this group of diseases is unknown. In the past, patients with chronic myeloid leukemia (CML) were included in this group of diseases, but cytogenetic and molecular studies revealed a unique causality of CML (related to Bcr-Abl). Now a similar phenomenon may be occurring with other myeloproliferative disorders.
JAK2 is a tyrosine kinase that has a major role in cell proliferation. Researchers have previously identified an acquired single point mutation as the probable cause of more than half the cases of myeloproliferative disorders.28 The hypothesis of this study was that mutated JAK2 could be responsible for myeloproliferative disorders. Researchers in the study performed molecular genetic studies in 73 patients with polycythemia vera, 51 with essential thrombocytosis, and 16 with idiopathic myelofibrosis. They found that 97% of patients with polycythemia vera had a single acquired mutation of JAK2 cytoplasmic tyrosine kinase. The same mutation was present in 57% of patients with essential thrombocytosis and 50% of patients with idiopathic myelofibrosis. They also found this mutation is all erythropoietin-dependent erythroid colonies and is present in multipotent cells, giving rise to both erythroid and myeloid cells. The authors suggest that identification of mutated JAK2 will assist in classification of myeloproliferative disorders and may provide insight into pathogenesis.
INCBO18424 is a Janus associated kinase (JAK) inhibitor that was evaluated in a phase I/II trial in 32 patients with primary myelofibrosis (PNF) and post polycythemia vera/essential thrombocythemia myelofibrosis.29 These researchers reported significant reduction (54%) of splenomegaly in 24 patients by one month and 76% of patients by three months. They also reported improvements in performance scores in most patients. One patient became transfusion independent. They also observed laboratory changes such as a reduction in JAK2V617F allele burden, reduction in proinflammatory angiogenic cytokines, and increases in hematopoietic growth factors. The authors described these results as “unprecedented” for patients with myelofibrosis.
Summary: ASCO 2008 delivered encouraging results in regards to recent progress in the treatment of hematologic malignancies. As individualized treatment options continue to advance, patients with both acute and chronic leukemias, MDS, and myeloprolific disorders will continue to benefit from these advancements.
References:

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2 Roy L, Guilhot J, Krahnke T, et al. Survival advantage from imatinib compared with the combination interferon-alpha plus cytarabine in chronic-phase chronic myelogenous leukemia: historical comparison between two phase 3 trials. Blood. 2006;108:1478-1484.
3 Mauro MJ, Baccarani M, Cervantes F, et al. Dasatinib 2-year efficacy in patients with chronic-phase chronic myelogenous leukemia (CML-CP) with resistance or intolerance to imatinib (START-C)). Journal of Clinical Oncology. 2008;26:abstract 7009.
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10 Rai KR, Moore J, Wu J, et al. Effect of the addition of oblimersen (Bcl-2 antisense) to fludarabine/cyclophosphamide for relapsed/refractory chronic lymphocytic leukemia (CLL) on survival in patients who achieve CR/nPT:Five –year follow-up from a randomized phase III study. Journal of Clinical Oncology. 2008;26:abstract 7008.
11 O’Brien S, Moore JO, Boyd TE, et al. Randomized phase III trial of fludarabine plus cyclophosphamide with or without oblimersen sodium (Bcl-2 antisense) in patients with relapsed or refractory chronic lymphocytic leukemia. Journal of Clinical Oncology. 2007;25:1114-1120.
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18 Lin TS, Andritsos LA, Fisher JB, et al. Activity of the cylin-dependent kinase (CPK) inhibitor flavopiridol in relapsed, genetically high risk chronic leukemia (CLL). Journal of Clinical Oncology. 2008;26:abstract 7007.
19 Pitini V, Arrigo C, Naro, et al. Subcutaneous low-dose alemtuzumab as first line therapy for elderly CLL patietns with delection of 17p. Journal of Clinical Oncology. 2008;26:abstract 7048.
20 Kirk R, Schultz W, Bowman P, et al. Improved early event-free survival (EFS) in children with Philadelphia chromosome-positive (PH+) acute lymphoblastic leukemia (ALL) with intensive imatinib in combination with high dose chemotherapy: Children’s Oncology Group (GOG) Study:AALL0031.
21 Thomas DA, Kantarjian HM, Cortes JE, et al. Outcome after frontline therapy with the hyper-CVAD and imatinib mesylate regimen for adults with de novo or minimally treated Philadelphia (PH) positive acute lymphoblastic leukemia (ALL). Journal of Clinical Oncology. 2008;26:abstract 7019.
22 Ravandi F, Faderl S, Thoma DA, et al. Phase II study of combination of the hyper CVAD regimen with dasatinib in patients (pts) with newly diagnosed Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia (ALL). Journal of Clinical Oncology. 2008;26:abstract 7020.
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29 Verstovsek S, Kantarjian HM, Pardanan A, et al. A phase I/II study of INCBO18424, an oral, selective JAK inhibitor, in patients with primary myelofibrosis (PMF) and post polycythemia vera/essential thrombocythemia myelofibrosis (Post PV/ET MF). Journal of Clinical Oncology 2008;26:abstract 7004